The goal of this proposal is to have the University of California at San Francisco (UCSF) continue as a TrialNet Clinical Center, with the ultimate long-term objectives to better understand the natural history and pathogenesis of type 1 diabetes mellitus (T1D), and to develop therapies to delay or prevent the onset of T1DM in those at risk, and to preserve remnant beta cell function in those with new onset T1D. UCSF is uniquely positioned to serve as a Clinical Center for TrialNet, given a well renowned clinical diabetes program; a large population base for subject recruitment; and a strong established track record with basic, translational, and clinical research on autoimmune interventions for T1D. In addition, the center has Clinical and Translational Science Institute (CTSI) funding, with both a Pediatric and General Clinical Research Center (PCRC, GCRC), and highly regarded investigators with extensive experience in both basic science and clinical research. We have made significant contributions to the TrialNet community on many different levels. We have greatly expanded our network and screening activities over the past 5 years, moving from 4 to the present 20 affiliates, with commensurate increase in enrollment of at risk subjects into monitoring and prevention trials. Specifically, the study goals are: Specific Aim 1: To optimize screening for the pathway to prevention protocol, and enroll at risk subjects into the monitoring phase of the protocol. To that end, we will maintain existing affiliates and partnerships while attempting to develop new partners. We will recruit, enroll, and retain at risk subjects within the Pathway to Prevention Study. Specific Aim 2: To screen and enroll eligible subjects into existing TrialNet prevention studies, and develop novel approaches to T1DM prevention.